PROJECT SUMMARY Traditional models of assessment have been found to lead to the misclassification of patients (specifically females and those mildly affected) with autism spectrum disorder (ASD). Heightened social behavioral traits have been found in females, suggesting that our current diagnostic tools (i.e. surveys, questionnaires, interviews, and ?gold standard? direct observation of social and communicative behaviors in affected individuals) may not be capturing the full distribution of social impairments across individuals with ASD with sufficient specificity. Thus, current assessment methods are limiting our ability to objectively assess sex differences as well as characterize protective factors in females versus males that influence diagnoses. We propose to test a hypothesis that appropriate autonomic nervous system (ANS) regulation in females serves as a protective factor against the development of clinical ASD features. We will test this hypothesis using a genetics-first approach in a cohort of patients with genetic copy number variantions (CNV) that are known to increase risk for ASD. Capturing distinct components across several measures of autonomic function and arousal state as it relates to quantitative clinical features could provide insight into the neurophysiologic mechanisms underlying phenotypic variability between females and males. We propose that measurement of ANS regulation will capture important variance that contributes to the reduction of behavioral manifestations of ASD in females. Previous research has highlighted the role of the ANS in generating arousal states and its potential involvement in deficits of social cognition and social impairment. One hypothesis is that males may be more susceptible to impairments in social skills due to a dysregulated ANS. In support of this hypothesis, gender differences in ANS function have been described, with heightened parasympathetic activity in females and reduced parasympathetic activity in males. While atypical arousal and ANS function have been observed in ASD, little is known regarding the way in which individual differences in ANS regulation are related to core diagnostic features of the ASD phenotype. Using a genetics first approach, we will quantitatively characterize individual differences in autonomic function across the ASD phenotype and investigate whether ANS regulation may serve to protect females from developing the severity of symptoms observed in males with ASD. Patients that have been identified as having a de novo copy number variant (CNV) (recruited for the parent proposal) will be asked to complete an online phenotyping battery to characterize autonomic function. We will also utilize an innovative strategy that capitalizes on Geisinger's long-standing electronic health record (EHR) to develop a coding scheme to assess the presence or absence of symptoms of autonomic function in patient participants. A model of dysregulated autonomic function in ASD may highlight how shifts in arousal may act as a protective mechanism and differentially predict the social traits of females and males with ASD.